par De Ridder, Mark;Verovski, Valeri N;Van Den Berge, Dirk L;Sermeus, Alexandra B L;Monsaert, Christinne;Wauters, Nathalie;Storme, Guy 
Référence International journal of radiation oncology, biology, physics, 57, 3, page (779-786)
Publication Publié, 2003-11
Référence International journal of radiation oncology, biology, physics, 57, 3, page (779-786)
Publication Publié, 2003-11
Article révisé par les pairs
| Résumé : | Purpose: Lipid A has shown promising immunostimulatory effects in both experimental tumor models and advanced stage cancer patients. This study examines whether lipid A may directly modulate the radioresponse of tumor cells by activating inducible nitric oxide synthase (iNOS) or cyclooxygenase-2 (COX-2) through nuclear factor-κB (NF-κB) signaling. Methods and Materials: Hypoxic EMT-6 tumor cells were exposed to lipid A and analyzed for the level of COX-2 and iNOS by Western blotting and enzymatic assays. The hypoxic radioresponse of EMT-6 cells was estimated by clonogenic survival. The activation of NF-κB was examined by immunostaining of its p65 subunit and by luciferase reporter gene assay. Results: Lipid A dose-dependently increased the expression and activity of iNOS with a maximal effect at plasma achievable concentrations of 3-30 μg/mL. The COX-2 mediated production of prostaglandin E2 was constitutively high and further upregulated by lipid A. The radiosensitivity of hypoxic EMT-6 cells was increased up to 2.5 times and counteracted by the iNOS inhibitor aminoguanidine but not by the COX-2 inhibitor NS-398. The mechanism of radiosensitization was linked to NF-κB signaling, because its inhibition by phenylarsine oxide impaired both iNOS activation and radioresponse. Conclusions: Lipid A is an efficient hypoxic cell radiosensitizer at plasma relevant concentrations, which provides a rationale to combine lipid A with radiotherapy in further studies. © 2003 Elsevier Inc. |
